Pomalidomide is a thalidomide analog. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure: The empirical formula for pomalidomide is C 13 H 11 N 3 O 4 and the gram molecular weight is 273.24. Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers. POMALYST is available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, and sodium stearyl fumarate. The 1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, and black ink. The 2-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3, and white ink. The 3-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, and white ink. The 4-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2, and white ink. pom-chem-structure

POMALYST is a thalidomide analogue indicated for the treatment of adult patients: • in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. • with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s)

Multiple Myeloma POMALYST, in combination with dexamethasone, is indicated for adult patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy

Kaposi Sarcoma POMALYST is indicated for the treatment of: • Adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART). • Kaposi sarcoma (KS) in adult patients who are HIV-negative. This indication is approved under accelerated approval based on overall response rate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

• Capsules:1 mg, dark blue opaque cap and yellow opaque body, imprinted "POML" on the cap in white ink and "1 mg" on the body in black ink • 2 mg, dark blue opaque cap and orange opaque body, imprinted "POML" on the cap and "2 mg" on the body in white ink • 3 mg, dark blue opaque cap and green opaque body, imprinted "POML" on the cap and "3 mg" on the body in white ink • 4 mg, dark blue opaque cap and blue opaque body, imprinted "POML" on the cap and "4 mg" on the body in white ink Capsules: 1 mg, 2 mg, 3 mg, and 4 mg

• MM: 4 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression. Refer to section 14.1 for dexamethasone dosing. • KS: 5 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression or unacceptable toxicity. • Modify the dosage for certain patients with renal impairment or hepatic impairment

Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST

Recommended Dosage for Multiple Myeloma The recommended dosage of POMALYST is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give POMALYST in combination with dexamethasone

Recommended Dosage for Kaposi Sarcoma The recommended dosage of POMALYST is 5 mg once daily taken orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS)

Dosage Modifications for Hematologic Adverse Reactions Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of POMALYST in patients with multiple myeloma (MM) when the neutrophil count is at least 500 per mcL and the platelet count is at least 50,000 per mcL. Dosage modification for POMALYST for hematologic adverse reactions in patients with MM are summarized in Table 1. Table 1: Dosage Modifications for POMALYST for Hematologic in MM Adverse Reaction Severity Dosage Modification * Permanently discontinue POMALYST if unable to tolerate 1 mg once daily. ANC= absolute neutrophil count Neutropenia • ANC less than 500 per mcL or febrile neutropenia (fever greater than or equal to 38.5°C and ANC less than 1,000 per mcL) • Withhold POMALYST until ANC is greater than or equal to 500 per mcL; follow CBC weekly. • Resume POMALYST dose at 1 mg less than the previous dose.* • For each subsequent drop of ANC less than 500 per mcL • Withhold POMALYST until ANC is greater than or equal to 500 mcL. • Resume POMALYST dose at 1 mg less than the previous dose.* Thrombocytopenia • Platelets less than 25,000 per mcL • Withhold POMALYST until platelets are greater than or equal to 50,000 per mcL; follow CBC weekly. • Resume POMALYST dose at 1 mg less than the previous dose* • For each subsequent drop of platelets less than 25,000 per mcL • Withhold POMALYST until platelets are greater than or equal to 50,000 per mcL. • Resume POMALYST at 1 mg less than the previous dose* Kaposi Sarcoma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of POMALYST in patients with KS when the neutrophil count is at least 1000 per mcL and the platelet count is at least 75,000 per mcL. Dose modifications for POMALYST for hematologic adverse reactions in patients with KS are summarized in Table 2. Table 2: Dosage Modifications for POMALYST for Hematologic Adverse Reactions in KS Adverse Reaction Severity Dosage Modification * Permanently discontinue POMALYST if unable to tolerate 1mg once daily. ANC= absolute neutrophil count Neutropenia ANC 500 to less than 1,000 per mcL Day 1 of cycle • Withhold POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at the same dose. During cycle • Continue POMALYST at the current dose. ANC less than 500 per mcL • Withhold POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at the same dose. Febrile Neutropenia ANC less than 1,000 per mcL and single temperature greater than or equal to 38.3°C or ANC less than 1,000 per mcL and sustained temperature greater than or equal to 38°C for more than 1 hour • Withhold POMALYST until ANC is greater than or equal to 1,000 per mcL. • Resume POMALYST at dose 1 mg less than the previous dose.* Thrombocytopenia Platelet count 25,000 to less than 50,000 per mcL Day 1 of cycle • Withhold POMALYST until platelet count is greater than or equal to 50,000 per mcL. • Resume POMALYST at the same dose. During cycle: • Continue POMALYST at the current dose. Platelet count less than 25,000 per mcL Permanently discontinue POMALYST

Dosage Modifications for Non-Hematologic Adverse Reactions Permanently discontinue POMALYST for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction . For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician's discretion

Dosage Modifications for Strong CYP1A2 Inhibitors Avoid concomitant use of POMALYST with strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg

Dosage Modification for Severe Renal Impairment on Hemodialysis Take POMALYST after completion of dialysis procedure on hemodialysis days . • For patients with MM with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily. • For patients with KS with severe renal impairment requiring dialysis, reduce the recommended dosage to 4 mg orally daily

Dosage Modification for Hepatic Impairment Multiple Myeloma For patients with MM with mild or moderate hepatic impairment (Child-Pugh A or B), reduce the recommended dosage to 3 mg orally daily. For patients with MM with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 2 mg . Kaposi Sarcoma For patients with KS with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C), reduce the recommended dosage to 3 mg orally daily

Administration Swallow capsules whole with water. Do not break, chew, or open the capsules. POMALYST may be taken with or without food.

• Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue. • Hematologic Toxicity: Neutropenia was the most frequently reported Grade 3/4 adverse event. Monitor patients for hematologic toxicities, especially neutropenia. • Hepatotoxicity: Hepatic failure including fatalities; monitor liver function tests monthly. • Severe Cutaneous Reactions: Discontinue POMALYST for severe reactions. • Tumor Lysis Syndrome (TLS): Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions. • Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue POMALYST for angioedema and anaphylaxis

Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death . POMALYST is only available through PS-Pomalidomide REMS . Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning POMALYST therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles, or every 2 weeks in females with irregular menstrual cycles . Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm . Blood Donation Patients must not donate blood during treatment with POMALYST and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

PS-Pomalidomide REMS Because of the embryo-fetal risk , POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), "PS-Pomalidomide REMS" . Required components of PS-Pomalidomide REMS include the following: • Prescribers must be certified with PS-Pomalidomide REMS by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements . • Pharmacies must be certified with PS-Pomalidomide REMS , must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about PS-Pomalidomide REMS is available at www.PS-PomalidomideREMS.com or by telephone at 1-888-423-5436

Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors

Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Hematologic Toxicity Multiple Myeloma In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia was the most frequently reported Grade 3 or 4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3 or 4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification . Kaposi Sarcoma In Trial 12-C-0047, hematologic toxicities were the most common (all grades and Grade 3 or 4) adverse reactions . Fifty percent of patients had Grade 3 or 4 neutropenia. Monitor patients for hematologic toxicities, especially decreased neutrophils. Monitor complete blood counts every 2 weeks for the first 12 weeks and monthly thereafter. Withhold, reduce the dose, or permanently discontinue POMALYST based on the severity of the reaction

Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered

Severe Cutaneous Reactions Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Consider POMALYST interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue POMALYST for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS

Dizziness and Confusional State In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice

Neuropathy In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial

Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of MM

Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with POMALYST. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Hypersensitivity Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to POMALYST have been reported. Permanently discontinue POMALYST for angioedema or anaphylaxis .

Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg ( 2.6 , 7.1 , 12.3 )

Drugs That Affect Pomalidomide Plasma Concentrations CYP1A2 inhibitors : In healthy subjects, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased C max and AUC of pomalidomide by 24% and 125% respectively . Increased pomalidomide exposure may increase the risk of exposure related toxicities. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine) . If co-administration is unavoidable, reduce the POMALYST dose .